Peripheral Bile Duct Paucity and Cholestasis in the Liver of a Patient With Alagille Syndrome

Abstract

Alagille syndrome (AGS) is a developmental, multiorgan disease caused by mutations of the Jagged1 gene. The liver is one of the major organs affected in AGS, and the hallmark of liver pathology in AGS is an age-related increase in the proportion of portal tracts that have no bile duct, but without evidence of prominent bile duct damage. The pathogenesis of this bile duct paucity is currently not well understood. (Immuno)histochemical and molecular analyses were performed on several liver biopsies that were taken during macroscopic examination of the explant liver of a 17-year-old AGS patient. The liver periphery was macroscopically pale and was microscopically characterized by complete absence of bile ducts and presence of severe cholestasis, but there was no ductular reaction. Conversely, the central, hilar portion contained normally developed bile ducts showing no or minimal damage and cholestasis. A missense mutation in the Jagged1 gene was present in both parts of the liver, indicating that mosaicism did not cause this peculiar picture. There was also a hypertrophy of the hepatic arterial branches in the liver periphery. Together with previous indirect findings, the current study of the explant liver of an AGS patient strongly suggests that a lack of branching and elongation of bile ducts during postnatal liver growth is the mechanism by which peripheral bile duct paucity and cholestasis develops in AGS. Our findings also suggest that anomalies of the intrahepatic arterial branches may be part of AGS in some patients.

Architectural changes during regenerative and ontogenic liver growth in the rat

“…It is well known that the maturation of the biliary system and thus that of the lobular arrangement are completed only postnatally 21. The hilar‐peripheral orientation of this process has been clearly demonstrated by the characterization of the liver of Alagille's patients 22. That is, a new layer of lobules might be formed postnatally.…”

Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice

“…The major bile duct branches, as examined here, do not appear to be affected by decreased Notch signaling mediated by Alb‐Cre. As in these mouse models, cases of AGS have been described with absence of bile ducts associated with cholestasis in peripheral areas, while hilar regions contain normally developed bile ducts 28. In addition, some older patients with AGS present with scintigraphic patterns of prolonged retention of tracer in peripheral regions, but normal clearance in hilar regions 29.…”

Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies

“…Moreover, its aberrant phosphorylation at the Ser675 of β-catenin in a mouse model of CHF/CD, act as protein stabilizer, impeding its phosphorylation and degradation [87] thus stimulating the secretion of profibrotic and proinflammatory mediators by cystic epithelia [64]. Another fundamental pathway involved in RDC proliferation is Notch [88], a signal mechanism requiring the cell-cell contact and particularly important in biliary differentiation and elongation along bile duct fetal development [28,89]; Notch (1 to 4) is a family of receptors for different ligands (Jagged, and Delta) that, once docked, allow the cleavage by γ-secretases of the notch internal cellular domain (NICD), that translocate to the nucleus to act as the transcription factor binding the recombinant signal binding protein for immunoglobulin kappa J (RBP-Jk) [17]. Notably, mutations of Notch2 or of its ligand Jagged1 are responsible for the development of Alagille syndrome, a recessive genetic disease characterized by a lack of biliary structures that fail to elongate from the hilum [89] and characterized by an accumulation of cells of intermediate hepato-biliary morphology [90].…”